Myostatin, or growth/differentiation factor 8 (GDF-8), belongs to the transforming growth factor-β (TGF-β) superfamily (McPherron, Lawler et al. 1997). The human myostatin gene has been cloned (Gonzalez-Cadavid, Taylor et al. 1998), and it has been reported that myostatin is largely expressed in human skeletal muscle and plays an essential role in negatively regulating the growth and development of skeletal muscle (Gonzalez-Cadavid, Taylor et al. 1998).
Knock-out mice provided the first evidence that myostatin plays a key role in negatively regulating muscle development (McPherron, Lawler et al. 1997). The myostatin null mice were normal except that they were significantly larger than wild-type mice and had a large and widespread increase in skeletal muscle mass. Furthermore, it was also determined that two breeds of cattle, with the heritable characteristic of increased muscle mass, have mutations in the myostatin coding sequence (McPherron and Lee 1997). Furthermore, the serum and intramuscular concentrations of myostatin are increased in HIV-infected men with muscle wasting compared with healthy men (Gonzalez-Cadavid, Taylor et al. 1998). These data support the role of myostatin as a negative regulator of skeletal muscle growth in adult men and as a contributor to muscle wasting in HIV-infected men.
Heretofore, methods for treating muscle-wasting conditions and/or enhancing muscle mass in mammals by manipulating myostatin levels have been proposed. For example, U.S. Pat. Nos. 6,103,466 and 6,617,440, and U.S. published patent application 20030074680 A1 disclose methods for inhibiting levels of expressed myostatin by administering to a human or animal subject, an antisense compound against the myostatin transcript. To date, there is no evidence that such approaches have succeeded or would succeed as disclosed, or how one would select and monitor subjects for and during treatment. There is thus a need for a treatment method for effectively treating muscle wasting as a result of a condition such as paralysis or disease state such as, for example, aging, acquired immune deficiency syndrome, multiple sclerosis, and cancer. There is also a need for an antisense agent that can effectively accumulate in target muscle cells, e.g., with oral administration, and inhibit myostatin expression in muscle cells.
Methods for enhancing muscle mass in meat-bearing animals, by administering anti-myostatin antisense agents, have also been proposed. However, to date such approaches have not proven practical because of poor uptake of the agents and/or inability to administer the agents orally. It would thus be desirable to provide an agent that could be supplied orally, e.g., in animal feed, to enhance muscle mass in meat-bearing animals.